Abstract 2879: Preclinical characterization of GT-00A x IL15: A novel IL-15-based immunocytokine with unique tumor targeting properties
Authors: Patrik Kehler, Anika Jaekel, Johanna Gellert, Christoph Goletz, Timo Lischke, Anke Flechner, Antje Danielczyk, Theresa Neumann
Journal: Cancer Research (2022)

Abstract Introduction: IL-15 is a potent pro-inflammatory cytokine that enhances the differentiation, proliferation and cytolytic activity of NK cells and T cells. Due to the huge potential of IL-15 to activate both innate and adaptive anti-tumor immunity, several IL-15-based immunocytokines are currently in clinical development. However, all of them preferentially act in the periphery and not locally within the tumor. To further increase the efficacy and safety of IL-15-based immunocytokines, we developed GT-00A x IL15, an immunocytokine targeting a tumor-associated, glycosylated epitope of MUC-1 (TA-MUC1). GT-00A x IL15 was designed to balance best tumor enrichment, efficacy and safety and thus represents a new cancer immunotherapeutic for the treatment of solid tumors with high medical need. Experimental procedures: GT-00A x IL15 was extensively studied in several in vitro assays to assess its activity and characterize its complex mechanisms of action. Several pharmacokinetic, pharmacodynamic, biodistribution and efficacy studies were performed in tumor-free or tumor-bearing mice to further analyze its pharmacological profile and efficacy in vivo. The safety of GT-00A x IL15 was assessed in a 4-weeks GLP toxicology study in rats. Results summary: We can demonstrate in vitro that targeting IL-15 to tumor cells by using GT-00A x IL15 increases the cytotoxic activity of effector cells against TA-MUC1-positive tumor cell lines compared to parental GT-00A and an untargeted IL-15 control construct. Further, GT-00A x IL15 mediates a dose-dependent infiltration of NK and T cells into MCF-7 tumor spheroids that is not observed using the controls. In a biodistribution study using radioactively labelled GT-00A x IL15, we observed significantly increased enrichment of GT-00A x IL15 in the tumor compared to the untargeted IL-15 control construct. This tumor enrichment translated into activation and expansion of tumor-infiltrating NK and CD8+ T cell effector cells and single agent efficacy in different tumor models in vivo. The safety assessment of GT-00A x IL15 in a dose-range finding study using rats as relevant species did not show any safety concerns so far. The full data package will be available early 2022 to be presented at the AACR meeting. Conclusions: Our results show that by using TA-MUC1 as a broadly expressed and highly tumor-specific antigen, we are able to direct IL-15 to the tumor. Local enrichment of GT-00A x IL15 within the tumor ultimately induced local effector cell activation and expansion. GT-00A x IL15 showed single agent efficacy in vivo with a good safety profile. These data highlight the potential of GT-00A x IL15 to increase the efficacy and safety of an IL-15-based immunocytokine by tumor targeting. GT-00A x IL15 shows great promise for the treatment of TA-MUC1-positive solid tumors either as monotherapeutic agent or as valuable combination partner. Citation Format: Patrik Kehler, Anika Jaekel, Johanna Gellert, Christoph Goletz, Timo Lischke, Anke Flechner, Antje Danielczyk, Theresa Neumann. Preclinical characterization of GT-00A x IL15: A novel IL-15-based immunocytokine with unique tumor targeting properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2879.